Survival outcomes of surgery for retroperitoneal sarcomas: A systematic review and meta-analysis

Background Definitive evidence to guide clinical practice on the principles of surgery for retroperitoneal sarcomas (RPSs) is still lacking. This study aims to summarise the available evidence to assess the relative benefits and disadvantages of an aggressive surgical approach with contiguous organ resection in patients with RPS, the association between surgical resection margins and survival outcomes, and the role of surgery in recurrent RPS. Methods We searched PubMed, the Cochrane Library, and EMBASE for relevant randomised trials and observational studies published from inception up to May 1, 2021. Prospective or retrospective studies, published in the English language, providing outcome data with surgical treatment in patients with RPS were selected. The primary outcome was overall survival (OS). Findings In total, 47 articles were analysed. There were no significant differences in the rates of OS (HR: 0.93; 95% CI: 0.83–1.03; P = 0.574) and recurrence-free survival (HR: 1.00; 95% CI: 0.74–1.27; P = 0.945) between the extended resection group and the tumour resection alone group. Organ resection did not increase postoperative mortality (OR: 1.00; 95% CI: 0.55–1.81; P = 0.997) but had a relatively higher complication rate (OR: 2.24, 95% CI: 0.94–5.34; P = 0.068). OS was higher in R0 than in R1 resection (HR: 1.34; 95% CI: 1.23–1.44; P < 0.001) and in R1 resection than in R2 resection (HR: 1.86; 95% CI: 1.35–2.36; P < 0.001). OS was also higher in R2 resection than in no surgery (HR: 1.26; 95% CI: 1.07–1.45; P < 0.001), however, subgroup analysis showed that the pooled HR in the trials reporting primary RPS was similar between the two groups (HR, 1.14; 95% CI, 0.87–1.42; P = 0.42). Surgical treatment achieves a significantly higher OS rate than does conservative treatment (HR: 2.42; 95% CI: 1.21–3.64; P < 0.001) for recurrent RPS. Conclusions For primary RPS, curative-intent en bloc resection should be aimed, and adjacent organs with evidence of direct invasion must be resected to avoid R2 resection. For recurrent RPS, surgical resection should be considered as a priority. Incomplete resection remains to have a survival benefit in select patients with unresectable recurrent RPS.


Methods
We searched PubMed, the Cochrane Library, and EMBASE for relevant randomised trials and observational studies published from inception up to May 1, 2021. Prospective or retrospective studies, published in the English language, providing outcome data with surgical treatment in patients with RPS were selected. The primary outcome was overall survival (OS).

Introduction
Soft tissue sarcomas (STS) are rare malignant tumours that most commonly arise from cells of mesenchymal origin and represents approximately 1% of all adult malignancies [1]. Approximately 15-20% of all STSs arise in the retroperitoneum [2]. STS consists of more than 70 welldefined histologic subtypes, and liposarcoma is the most common one found in the retroperitoneum [2]. Other subtypes include leiomyosarcoma, MFH, solitary fibrous tumors and malignant peripheral nerve sheath tumors [2]. Individual histologic subtypes have unique behavioral characteristics and treatment outcomes. Although STS of the retroperitoneum are rare, these tumours have worse prognosis than those arising from the trunk or extremity, with 5-year overall survival (OS) rates of 39-70% [3]. Several factors influence this poor prognosis. First, retroperitoneal sarcomas often progress asymptomatically and are thus only detected incidentally when the substantially enlarged tumour compresses the surrounding organs [4]. Patients presenting with back pain or abdominal distention already have a large tumour with multi-organ involvement and close proximity to critical structures such as major vessels or kidney. Second, surgical resection of localised tumours with gross negative margins remains the mainstay of curative treatment for patients with primary retroperitoneal sarcomas (RPSs) [5]. However, a significant percentage of patients, even those treated at high-volume centres with gross negative margins, develop disease recurrence [6]. Besides, recent multicentre randomised controlled trials (RCTs) have reported similar rates of abdominal recurrence-free survival (RFS) and OS between surgery alone and preoperative radiotherapy plus surgery [7]. Adjuvant chemotherapy is not routinely recommended in RPS because of lack of sufficient evidence supporting its OS benefit [3]. Third, RPS has over 70 different histologic subtypes, and the heterogeneity in its biological behaviour, treatment response, and oncological risks renders a homogeneous therapeutic approach difficult and makes it challenging to develop evidencebased guidelines [8]. Surgery for primary or recurrent RPS is still technically challenging [5]. Thus, margin assessment continues to be an area of uncertainty in RPS surgery. Actual pathologic evidence of organ invasion is rare, and thus, the appropriateness of resecting adjacent uninvolved organs in RPS surgeries is still controversial [9]. Aggressive resection to grossly uninvolved organs may improve R0 resection rates; however, the benefit of converting R1 to R0 resections is unclear, and concomitant organ resection might be associated with an increased risk of postoperative complications [10]. Currently, local recurrence is the primary cause of mortality in RPS, with up to 75% of mortalities occurring without evidence of distant metastases [11]. Although R2 resection is not recommended for primary RPS, some study suggested that R2 resection may prolong survival and alleviate symptoms in select patients with unresectable RPS [12]. Further, data regarding the outcomes of surgery for recurrent RPS and data to guide treatment decisions for patients with local recurrence are limited.
Thus, we aimed to gather available evidence to determine the relative benefit and disadvantages of an aggressive surgical approach with contiguous organ resection in patients with RPS.
We also compared the long-term survival rates among different surgical resection margins for RPS and the OS rates between surgery and conservative treatment in patients with recurrent RPS.

Search strategy
This systematic review and meta-analysis was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines for systematic reviews [13]. We searched PubMed, the Cochrane Library, and EMBASE for relevant studies published from inception up to May 1, 2021 using the following keywords: 'retroperitoneal tumour' or 'retroperitoneal neoplasm' or 'retroperitoneal sarcoma' and 'surgery' or 'surgical' or 'resection' (specific search strategies are listed in S1 File).
We included randomized trials and observational studies comparing different surgical resection margins for RPS; comparing surgery with conservative treatment for recurrent RPS patients; and comparing extended resection including adjacent organs with resection of tumour alone. Conference abstracts, letters, editorials, or any publication other than a peerreviewed original research article or a technical report from a national public health organization and those that did not provide hazard ratios (HRs) or confidence intervals (CIs) were excluded. Studies were also excluded if the study population was duplicated in another study included in our meta-analysis. In case of duplicate populations, the study that included more institutions or more patients was selected. Only studies published in the English language were included, and the references of the selected articles were reviewed for additional relevant studies.

Data extraction and quality assessment
Two authors (Q.G. and X.D.) independently selected the studies based on the inclusion and exclusion criteria. After the initial search, the titles and abstracts were independently screened to identify potentially relevant studies that were then submitted to a full-text review. Disagreements were resolved by discussion with a third reviewer (J.Z.). The following data were compiled in a spreadsheet: (1) study characteristics (name of the first author, publishing year, study design, sample size); (2) tumour characteristics (histologic subtype, French Federation of Cancer Centers Sarcoma Group [FNCLCC] grade [14], tumour status); (3) surgical characteristics (combined organ resection, margin status, vascular reconstruction); (4) adjuvant therapy (radiotherapy/chemotherapy), and (5) outcomes (OS, RFS, postoperative complications, and 30-day mortality). When data were unavailable, efforts were made to contact the corresponding author to obtain the missing data.
The methodological quality of the studies was assessed using the Newcastle-Ottawa Scale [15]. The scale evaluates study bias and assigns points in the following three domains: patient selection, comparability, and outcomes. Each reviewer generated a score, and the value was reviewed (Q.G. and J.Z.). Studies with a high risk of bias (score <6) were further reviewed for inclusion.
compare the risk of recurrence or OS. Pooled odds ratios (ORs) with 95% CIs were estimated to compare the risk of postoperative complication or early postoperative mortality between an aggressive surgical approach with contiguous organ resection and tumour resection alone. For time-to-event outcomes, including RFS and OS, HRs and their associated variances were extracted, or estimates were calculated where possible using the methods described by Tierney et al [16]. Prespecified subgroup analyses by tumour status (primary/recurrent) were performed. Sensitive analyses that only including studies with similar surgical margins were also performed. Publication bias was assessed using funnel plots. All statistical analyses were performed using Stata/MP, version 16.0 (StataCorp LLC). All tests were two sided, and P<0.05 was considered statistically significant.
Fatal outcomes related to operation were reported in seven trials (2643 participants) [10,19,22,44,51,57,59], but four of them reported no events in either group [10,22,44,51]. Three studies [19,57,59] reported 44 surgery-related deaths (22 in the extended resection group and 22 in the tumour resection alone group). The overall surgery-related mortality rate was 2%. The pooled analysis of the three trials did not show a significant difference between the extended resection group and tumour resection alone group (OR: 1.00, 95% CI: 0.55-1.81; P = 0.997; S1 File). Sensitive analyse that only including studies [59] with similar surgical margins also showed no significant difference between the extended resection group and tumour resection alone group (OR: 0.95, 95% CI: 0.57-1.76; P = 0.877).

Impact of surgery on long-term survival in recurrent RPS
A total of five studies [8,29,37,39,58] reported data on surgery versus conservative treatment for recurrent RPS. The results from these studies demonstrated that surgical treatment achieves a significantly higher OS rate than does conservative treatment (HR: 2.42; 95% CI: 1.21-3.64; P < 0.001; Fig 4), with moderate to high heterogeneity (I 2 = 64%).

Discussion
Guidelines on the management of RPS are still lacking owing to its low incidence. In this study, an aggressive surgical approach with contiguous organ resection achieved acceptable rates of postoperative complication and mortality in both primary and recurrent RPS. The results of this study also demonstrated the importance of surgery and surgical margins in long-term survival. To our best knowledge, this is the largest and most comprehensive metaanalysis focusing on the role of surgery in RPS.
The first consensus on the management of primary RPS was published by the trans-Atlantic RPS working group (TARPSWG) in 2015 [62]. In the follow-up, the group included several more European and North American centres and further improved the consensus on recurrent and metastatic RPS [63,64]. However, definitive evidence to guide clinical practice is still lacking. Multimodality treatment involving radiotherapy and/or chemotherapy is recommended to obtain negative surgical margins with a subsequently better local disease control and longer survival in STS in the extremity [4]. However, the use of adjuvant radiotherapy and chemotherapy in STS in the retroperitoneum varies widely among institutions because of the lack of high-level evidence supporting the benefit of these modalities [62,65]. A meta-analysis of ten non-RCTs concluded that perioperative radiation therapy is associated with higher OS and lower recurrence rates [66]. However, a recent multicentre RCT that compared between preoperative radiotherapy plus surgery and surgery alone for patients with primary RPS reported conflicting results [7]. There are also limited evidence on the usefulness of neoadjuvant therapy for recurrent RPS patients indicated for resection. In addition, radiotherapy to the retroperitoneum is a complex procedure. RCTs are needed to standardise the radiotherapy protocol for recurrent/unresectable RPS.
Given the lack of data, surgical resection remains the cornerstone of therapy and the only potentially curative therapy for patients with RPS. However, many aspects of surgical resection for RPS are controversial. For example, the efficacy of contiguous organ resection and the appropriate extent of curative-intent surgical resection are yet to be determined. Further, the role of gross incomplete resection for unresectable RPS needs to be clarified. The criteria for unresectability remains undefined, and the indication and eligibility for surgical resection vary by medical centre. Patients with residual macroscopic disease are often referred to specialised centres because they are a significant challenge from a surgical standpoint as the appropriateness of en bloc resection for organs adherent to the tumour needs to be determined intraoperatively [67]. The TARPSWG recently updated the consensus on management of primary RPS in adults [68]. The update mentioned criteria for technical non-resectability as involvement of the superior mesenteric artery, aorta, coeliac trunk, and/or portal vein; bone involvement; growth into the spinal canal; invasive extension of retrohepatic inferior vena cava leiomyosarcoma into the right atrium; infiltration of multiple major organs (eg, liver and pancreas) and/or major vessels. However, vascular reconstructions, which enable radical resection of retroperitoneal sarcomas in patients with advanced disease, have been successfully performed in many studies [69,70]. Further, complex surgeries are associated with an acceptable rate of serious perioperative complications [69]. In addition, a previous study indicated that more than one third of the patients with primary/recurrent RPS undergoing palliative-intent operation could achieve R0/R1 resection [31]. Thus, unresectability cannot be determined via computed tomography imaging alone, and patients should be referred to specialised centres and carefully evaluated by an experienced multidisciplinary team before any surgical resection is attempted. Furthermore, our results showed that even R2 resection achieves superior OS to no surgery, and surgical treatment achieves a significantly higher OS rate than does conservative treatment in recurrent RPS. These findings indicate that surgical resection should be considered as first-line treatment regardless of the tumour status (primary or recurrent).
With respect to the impact of organ resection, our findings indicated that rates of postoperative mortality are not significantly different between extended resection group and tumour resection alone, however, extended resection group had a relatively higher complication rate than the tumour resection alone group. In addition, organ resection did not improve local recurrence or OS. Given the importance of a quality surgical resection, early techniques ascribed to an aggressive surgical approach whereby adjacent uninvolved organs are routinely resected en bloc to optimise the margin status [20]. These techniques are referred to as compartmental resection [20]. Complete compartmental resection is defined as a systematic resection of uninvolved contiguous organs [20]. In general, the patient undergoes an en bloc tumour resection with the colon in front, the kidney inside, and the psoas at the back. Vessels are exposed after removal of adventitia, but the pancreas and duodenum are not resected if they are not involved. In contrast, contiguous organ resection is defined as resection of macroscopically involved adjacent organs [20]. Theoretically, complete compartmental resection could obtain a rim of normal tissue surrounding the tumour to ensure a better margin. However, compartmental resection only results in a lower local recurrence rate and is associated with a higher overall complication and lesser survival benefit than complete resection and contiguous organ resection [20,51]. These results might be explained by the following reasons. Both compartmental resection and contiguous organ resection have no impact on surgical resection margins, especially R0 resection [51]. The R0 resection is only approximately 57% in compartmental resection [51]. Unlike the more common epithelial tumours or adenocarcinomas, which develop within a single organ, RPS can infiltrate multiple surrounding organs owing to their large size and multiple central location [9,44]. Tumours measuring 20 cm on average have poorly defined anatomic borders, and thus, it would impractical to assess margin status [4]. In addition, it is challenging to obtain clear margins because RPS tumours are commonly surrounded by both anterior and posterior great vessels, vertebral column, and lumbar musculature. As such, although complete macroscopic surgical resection can be achieved in RPS, the incidence of local recurrence and disease progression remains high [39]. Determining the need for resection of adjacent organs depends on the surgeon's assessment of the extent of tumour invasion. Thus, understanding the survival benefit of radical excision of adjacent organs is crucial. As such, it is important that the need for extended resection is recognised pre/intraoperatively by multidisciplinary evaluation.
Consistent with previous studies [35,46], we found that surgical resection margins are correlated with long-term survival. The current meta-analysis indicated that OS was higher in R0 resection than in R1 resection and in R1 resection than in R2 resection. Similar findings were obtained in subgroup analysis by tumour status. R2 resection achieved a superior OS to no surgery. However, interestingly, the pooled HR in the studies on primary RPS showed a similar OS between the R2 resection group and the no operation group. This could be because patients with unresectable primary RPS might have higher TNM stage or histological grade, which could be associated with worse long-term outcomes. Thus, for these patients, owing to the similar rates of postoperative complication and mortality between extended resection and tumour resection alone, adjacent organs with evidence of direct invasion must be resected en bloc to avoid R2 resection. In contrast, incomplete surgical resection was beneficial for patients with recurrent RPS, prolonging survival and alleviating symptoms [12].
The strengths of our review include its comprehensive search and methodologic robustness. We searched all available literature to exclude studies with overlapping cohorts and analysed large-scale studies. However, the present study also had some limitations. First, selection bias is inevitably associated with this type of surgical studies, especially when the indication and eligibility for surgical resection and the method of assessment of appropriate resection margins might vary by medical centre. The FNCLCC grade, tumour status, and adjuvant therapy also varied among the studies, possibly introducing bias. Although we performed subgroup analysis to investigate the impact of tumour status, we were unable to evaluate other factors that may modify the association between different surgical strategies and survival outcomes (eg, histologic subtype and adjuvant therapy) because the relevant data were lacking. Second, there was an insufficient number of studies on extended resection (eg, adjacent organs vs tumour resection alone) and surgical treatment vs conservative treatment for recurrent RPS were insufficient, and thus, the recommendations for these comparisons have a relatively weak power. Subsequent long-term prospective studies in these areas are needed. Third, the included studies were limited to the literatures published in English. This strategy might lead to limited data collection. Finally, all trials included in this study used an open-label design, which might introduce bias. However, assessment of the methodological quality of the included studies indicated that most studies had a low or medium risk of bias.
In summary, RPS is a rare and complex malignancy that is best managed by an experienced multidisciplinary team in a specialised referral centre. Surgical resection should be attempted in majority of the patients. Primary RPS should be indicated for curative-intent en bloc resection with optimal extent of resection, and adjacent organs with evidence of direct invasion must be resected en bloc to avoid R2 resection. Routine compartmental resection is not recommended. Meanwhile, a part of unresectable recurrent RPS should be indicated for incomplete resection or debulking to improve survival after multidisciplinary evaluation.
Supporting information S1 File. It contains all the supporting tables and figures. (DOC)